Epidermis and hair are perpetually renewing tissues that become terminally differentiated. These two related tissues function to prevent water and heat loss, and to resist mechanical, chemical, and microbial assaults. Although some skin-specific proteins and their genes have been isolated and characterized, little is known about the genes that control differentiation or that control the expression of, or encode, genes specific to these tissues. The recent completion of the sequence of a large part of the human genome, the rapid acquisition of data about the mouse genome, as well as the compilation of libraries of genes expressed in specific tissues make the use of bioinformatic tools to identify and characterize skin-specific genes particularly attractive and appealing. We will use the EST (expression sequence tag) cluster expression collection provided by the Unigene databases of mouse and human sequences to identify genes predominantly or exclusively expressed in skin. A parallel analysis will be conducted using the Digital Differential Display tools, available in the CGAP database, to identify those genes that are expressed more abundantly in skin, but are also expressed in other tissues, as many crucial skin regulators may fall in this category. We have already identified approximately 1500 mouse skin clusters and a smaller number of human clusters that are highly or exclusively expressed in skin. The temporal and spatial distribution of expression will be analyzed by RNA in situ hybridization in the mouse embryo at different stages, in postnatal mouse skin, and in human embryonic, fetal and adult skin. Genes will be mapped either by bioinformatic procedures or by radiation hybrid mapping to identify candidates for yet uncharacterized genetic disorders. These studies should identify a significant proportion of the genes uniquely or predominantly expressed in skin that play the major roles in development and differentiation, thus set the stage to understand the full developmental program of the skin, and identify candidate genes for uncharacterized inherited human disorders of skin and hair.